This proposal is a competing renewal for a project, extant since 1988, that has chartered the natural and treated history of injecting drug users and the infections and illnesses, primarily HIV-related, to which they are subject. The current renewal proposes four major aims: (1) To evaluate temporal trends in HIV incidence, and determine period-specific risk factors and attributable risks associated with illicit drug use and sexual behaviors in a cohort of male and female HIV seronegative IDUs. Using hierarchical modeling, they will identify relative and attributable risks associated with macro-level risk factors (such as neighborhood social disadvantage and heroin purity) compared to individual-level HIV risks; (2) To characterize the natural history of illicit injection drug use, including behavioral and sociodemographic factors associated with initiation, relapse, and cessation, taking into account cohort and period effects across the lifespan using Cox and Poisson regression; (3) To determine incidence and temporal trends in morbidity and mortality among HIV seronegative IDUs associated with illicit drug use and co-morbid conditions compared to a parallel cohort of HIV-infect IDUs, to differentiate between morbidity related to HIV and HAART compared to drug use itself; (4) To determine HCV treatment eligibility among HCV-infected IDUs and identify individual and environmental barriers associated with access and utilization of treatment among treatment-eligible IDUs using a case-crossover design.